Process for preparing 3, 4-dihydro-4-hydroxy-2h-1, 3-benzoxazine-2-ones



United States Patent 3,385,851 PROCESS FOR PREPARING 3,4-DlHYDRO-4- HYDROXY 2H 1,3 EENZOXAZINE 2- ONES Richard E. Strube, Alexandria, Va., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Original application Mar. 27, 1964, Ser. No. 355,466, now Patent No. 3,296,259. Divided and this application Oct. 17, 1966, Ser. No. 586,939

3 Claims. (Cl. Z6(l244) This application is a division of application Ser. No. 355,466 filed Mar. 27, 1964, now US. Patent No. 3,296,259.

This invention pertains to novel organic chemical compounds and a process for preparing the same. The invention is more particularly directed to novel 3,4-dihydro-4- hydroxy-3-lower-alkyl-2H-1,3 benzoxazin 2 ones and 3,4-dihydro-4-hydroxy 3 phenyl-2H-l,3-benzoxazin-2- .ones, and a novel process for preparing the same by reacting a Z-hydroxybenzaldehyde with a loweralkyl isocyanate or phenyl isocyanate, and a novel process for preparing Z-hydroxybenzylamines.

The novel 3,4-dihydro-4-hydroxy-2H-1,3-benz0Xazin-2- ones of this invention can be represented by the following structural formula:

wherein R is selected from the group consisting of benzo and from zero to not more than 4 members selected from the group consisting of alkyl of not more than 3 carbon atoms, alkoxy of not more than 3 carbon atoms, loweralkylcarbamyloxy, phenylcarbamyloxy, halogen, and nitro; and X is selected from the group consisting of loweralkyl and phenyl. Examples of loweralkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and .octyl and the isomeric forms thereof; examples of halogen include fluorine, chlorine, bromine, and iodine; examples of alkyl of not more than 3 carbon atoms are methyl, ethyl, propyl, and isopropyl; and examples of alkoxy of not more than 3 carbon atoms are methoxy, ethoxy, propoxy, and isopropoxy. The benzo group can be in the 5,6-, 6,7-, or 7,8-positions.

The novel 3,4-dihydro-4-hydroxy-2H-1,3-benzoxazin-2- ones of Formula I are provided according to the novel r process of the invention by reaction of a 2-hydroxybenzaldehyde with a loweralkyl isocyanate or phenyl isocyanate in the presence of a basic catalyst and an inert reaction medium. The reaction proceeds readily with 2- hydroxybenzaldehydes of the formula:

H II

wherein R is selected from the group consisting of benzo and from zero to not more than 4 members selected from the group consisting of alkyl of not more than 3 carbon atoms, alkoxy .of not more than 3 carbon atoms, hydroxy, halogen, and nitro.

The reaction proceeds readily in the presence of an inert reaction medium containing a catalytic amount of a base. In general, stoichiometric amounts of the reactants are employed, although a slight excess of either 3,385,851 Patented May 28, 1968 reactant can be employed if desired. When R is hydroxy account should be taken of the fact that it will be acylated to a loweralkylcarbamyloxy or phenylcarbamyloxy group. Stoichiometrically, for each mole of the Z-hydroxybenzaldehyde, one mole of the required isocyanate is required when R is other than hydroxy, and at least two moles when R is hydroxy. Advantageously, the reaction is carried out between about 0 C. and about 0., preferably between about 15 C. and about 50 C. The rate of reaction is greater at the higher temperatures and the reaction is completed in less time, but side reactions are more likely to occur. Ordinarily it will not be necessary or desirable to use temperatures higher than about 50 C.

Suitable inert reaction media include diethyl ether (preferred), diisopropyl ether, toluene, benzene, tetrahydrofuran, dimethylformamide, chloroform, and the like. Suitable bases for catalyzing the reaction include trimethylamine, triethylarnine (preferred) and like trialkylamines, sodium hydroxide and like alkali metal hydroxides, the corresponding ethoxides and like alkoxides, sodium amide and like alkali metal amides, pyridine, picoline, collidine, dimethylaniline, and like basic amino compounds, tetramcthylammonium hydroxide and like quaternary ammonium bases, and the like.

The 3,4 dihydr0-4-hydroXy-2H-1,3-benzoxazin-2-ones of the invention are readily recovered from the reaction mixture, since they are relatively insoluble in cold media of the kind indicated above, and they readily separate in solid form. The solids are conveniently recovered on a filter and purified by recrystallization if desired.

A great variety of Z-hydroxybeuzaldehydes can be used in the process of the invention for preparing 3,4-dihydro- 4-hydroxy 2H 1,3-benzoXazin-2-ones. Representative suitable Z-hydroxybenzaldehydes include:

Tree

Z-hydroxyb enzaldehyde,

2-hydroxy-3 -methoxybenzaldehyde,

5 -chloro-2-hydroxybenzaldehyde, 5-bromo-2-hydroxybenzaldehyde, 2-hydroxy-S-nitrobenzaldehyde,

3,5 -dichloro-2-hydroxybenzaldehyde, 3-bromo-4-fluoro-2-hydroxybenzaldehyde, 6-fiuoro-2-hydroxy-5-nitrobenzaldehyde,

3 -bromo-4-chloro-2-hydroxy-5-nitrobenzaldehyde, 2-hydroxy-3 -methylbenzaldehyde, 2-hydroxy-3,4,6-trimethy1benzaldehyde, 2-hydroXy-4,5,6-trimethylbenzaldehyde,

5 -ethyl-2-hydroxy-3-methylbenzaldehyde, 4,6-dimethyl-2-hydroxybenzaldehyde,

3 ,5 -dibromo-4,6-dimethyl-2-hydroxybenzaldehyde, 2-hydroxy-4-methoxy-3-methylb enzaldehyde, 3-ethoxy-2-hydroxybenzaldehyde, 4,5,6-trimethoxy-2-hydroxybenzaldehyde, 4,6-diethoxy-3-ethyl-2-hydroxybenzaldehyde, 4-ethoxy-5-ethy1-6-methoxy-2-hydroxybenzaldehyde, 5-methoXy-3 ,4,6-trimethy1-2-hydroxybenzaldehyde, 3-propyl-2 hydroxybenzaldehyde, 3-isopropyl-5-nitro-2-hydroxybenzaldehyde, 5-chloro-4,6-dimethyl-Z-hydroxybenzaldehyde, 3-bromo-2-hydroxy-5-methoxybenzaldehyde, 2-hydroXy-6-methoxy-5-nitrobenzaldehyde, and 4,6-dimethoxy-Z-hydroxybenzaldehyde.

The 3,4 dihydro-4-hydroxy-2H-1,3-benzoxazin-2-ones of this invention (compounds of Formula I) are pharmacologically active as sedatives in mammals, birds, and other animals. The compounds are also useful as intermediates for preparing 2-hydroxybenzylamines, a known class of useful compounds.

The 2-hydroxybenzylamines are obtained by hydrogenolytically cleaving the 3,4-dihydr.o-4-hydroxy-2H-1,3-

benzoxazin-Z-ones of Formula I with lithium aluminum hydride according to the following equation:

wherein X, R and R are as defined above (except when R is nitro, in which caseR' can be reduced R).

The hydrogenolysis is conveniently accomplished in an inert reaction medium, for example, tetrahydrofuran (preferred), dioxane, dibutyl ether, diisopropyl ether, N-ethylcrystallized from a suitable solvent such as benzene, water, ethanol, dioxane-water, and the like.

By using the following 2-hydroxybenzaldehydes as starting compounds:

there were obtained, respectively, the compounds listed in morpholine, and the like. An excess of lithium aluminum the following table:

TABLE I Moles, Anhydrous Reaction M.P.C., Ca1cd., Found 2H-1,3-benzoxazin-2on0 aldehyde ether, ml. time, hrs. ((100) Example 1:

A 3, 4dihydro4.hydroxy-3-methyl 0.25 200 48 123 60.33 5. 06 7.82 00.40 5.00 7.00 B S-methoxy-3, 4-dil1ydro-4-hydroxy-3-mcthyl 0.20 200 48 150-158 o 6-chloro-3,4-dihydro-4-hydroxy'3-methyl 0.20 100 is 110-171 50150 3178 0150 50.83 3.83 0.40 D 6-bromo-3,4-dihydro4-hydr0xy-3-methyl 0.10 300 48 175-177 21.22 E 6-11itr0-3,4-dihydro-4-hydroxy-3-methyl 0.024 300 is use-133.5 48122 3100 12150 48.28 3.40 12.10 F G-methylearbamyloxy-Zi,4-dihydrol-hydroxy-3-methyl. 0.15 150 96 177-178 o 6,8-dichloro-3,-dihydro-i-hydroxy-tE-methyl. 0.10 250 24 c 179-180 as 2185 5105 11 5,(theme-3,4-dihydro-4-hydroxy-3-mcthyl 0.20 300 24 d 180-181 s's ii i1 31 e Recrysatallized from benzene. Instead of using 120 g. 01:1 50% CliaNCO solution in toluene per mole From Water. of aldehyde, 240 gjmole was added. From ethanol. 8 Instead olusing, 120 g. 0121 50%CU1NCO solution in toluene per mole of From dioxane-water. aldehyde, 160 g./n1ole was added (see below). Not recrystallized.

hydride is slowly added to the reaction mixture with The reaction of 5-nitro-2-hydroxybenzaldehyde with stirring, and the mixture is then heated, conveniently, on methyl 1socyanate in Example 1E led to the formation a steam bath or at the reflux temperature of the reaction of two compounds. After 24 hrs. yellow-orange crystals mixture. When the reaction is completed, the reaction mix- 40 were present in the reaction mixture. After another 24 ture is decomposed with aqueous alkali, and the Z-hyhrs. standing, long white needles were also present. These droxybenzylamine is recovered by conventional procedures products were separated by using chloroform in which such as solvent extraction followed by distillation or the needles readily dissolved. There was thus obtained solvent evaporation. The Z-hydroxybenzylamine product 2.2 g. of 6-nitro-3,4-dihydro-4-hydroxy-3-methyl-2H-1,3- can be purified by conventional methods such as recrystalbenzoxazin-Z-one as yellow-orange crystals, M.P. 183- lization or distillation under reduced pressure. 183.5 C. (dec.) after recrystallization from ethanol; and

The free base Z-hydroxybenzylamines of Formula III 0.35 g. of 6-nitro-3,4-dihydro-4-methylcarbamyloxy-3- can be reacted with fiuosilicic acid to form fluosilicate methyl-ZH-I,3 benzoxazin-2-one as white crystals, M.P. salts in accordance with U.S. Patents 1,915,334 and 2,075; 165-166 C. (dec.). 359. The amine fiuosilicate salts thus obtained are effec- The latter product was obtained in high yield accordtive as moth-proofing agents. The same free base cotlning to the following example: pounds also form salts with thiocyanic acid, which sa ts can be condensed with formaldehyde in accordance with Example g g 'gi hg l g U.S. Patents 2,425,320 and 2,606,155 to form amine enZOXaZm' thiocyanate-formaldehyde condensation products for use A mixture of 21.5 g. (0.13 mole) of 5-nitro-2-hydroxyas pickling inhibitors. They also form salts with trichloro- 'benzaldehyde, 250 ml. of chloroform, 30 ml. of a acetic acid which are active as herbicides, for example, solution of methyl 1socyanate (0.24 mole) in toluene, against Johnson grass, yellow foxtail, green foxtail, Berand 1.0 ml. of triethylamine was left at about 25 C. muda grass, and quack grass. for 48 hrs. The white crystals present were removed by The invention may be more fully understood by referfiltration. By adding diethyl ether to the mother liquor ence to the following examples in which the parts and an additional amount of product precipitated. The solpercentages are by weight unless otherwise specified. vent was evaporated under reduced pressure. The residue E X a m p16 1 was dissolved in 250 ml. of chloroform and treated with 1 ml. of triethylamine and 30 ml. of a 50% solution A faction mixture is P p y mixing a Solution of of methyl isocyanate in toluene, as described above. There the Starting 2-hydfm4ybt5n2a1dfihyde in anhydl'ous diethyl was obtained atotal yield of 29.7 g. of 6-nitro-3,4-dihydroether with a 50%solution of methyl isocyanate in toluene 4 methylcarbamyhxy 3 h l 2H 1 3 h and triethylamine. The 50% solution of methyl 1socyanate i 2- e, M P, 165-166 C. (dec.). in toluene is added in the proportions of 120 g. for each l .c l f CUHHNSOS; C, 4 9 H, 394; mole of the starting Z-hydroxybcnzaldehyde. This pro- N, 14 94 d; C, 4 32 11 334; N, 14 54 "ides a slight .excess of mathyl isocyanate l Example 3.-Alternative preparation of 3,4-dihydro-4- moles methyl 1socyanate per mole of the starting 2 -nyhydroxy 3 methyl 2H 1,3 benzoxazin 2 one droxybenzaldchyde. The reaction mixture is sealed 1n a and hydrogenolysis thereof flask and set aside at room temperature (about 25 C.) for a period of time ranging from 24 hrs. to 96 hrs. The PART A crystals which precipitate are filtered and, if desired, re- A mixture consisting of 30.5 g. (0.25 mole) of 2- hydroxybenzaldehyde, 200 ml. of anhydrous diethyl ether, 37.5 ml. of a 50% solution of methyl isocyanate in toluene (0.26 mole methyl isocyanate), and 0.5 ml. of triethylamine was heated at the reflux temperature for 2 hrs. After cooling the reaction mixture to about 25 C., a white solid that had separated was recovered on a filter. There was thus obtained 25.0 g. (55.8% yield) of 3,4 dihydro 4 hydroxy 3 methyl 2H 1,3- benzoxazin-Z-one, having a M.P. of l23-l24 C. (dec.).

PART B.-N, NDIMETHYL-2-HYDROXYBENZYLAMINE A sample of 3,4-d ihydro-4-hydroxy-3-methyl-2H-1,3- benzoxazin-Z-one (9.0 g.; 0.05 mole) prepared in Part A, above, was dissolved in 250 ml. of tetrahydrofuran (freshly distilled after refluxing for 3 hrs. with lithium aluminum hydride). To the stirred solution 5.0 g. of lithium aluminum hydride was added in small portions over an interval of 2 hrs. The mixture was then heated on a steam bath for hrs. After cooling the reaction mixture to about C., 20 ml. of 5% aqueous sodium hydroxide solution was carefully added. The decomposed reaction mixture was then extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the ether was removed by distillation. There was thus obtained 3.5 g. of N,N-dimethyl-2- hydroxybenzylamine as an oil, B.P. ll0l12 C. at 22 mm. of mercury pressure.

Analysis.-Calcd. for C H NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.24; H, 8.40; N, 8.86.

Example 4 Following the procedure of Example 3, but replacing methyl isocyanate with ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, pentyl isocyanate, hexyl isocyanate, isohexyl isocyanate, and octyl isocyanate there are obtained:

respectively, and the corresponding methyl-Z-hydroxybenzylamines, namely,

N-loweralkyl-N- (A') N-ethyl-N methyl-2-hydroxybenzylamine,

(B') N-propyl-N-methyl-2-hydroxybenzylamine,

(C') N-is0propyl-N-methyl-2-hydroxybenzylamine, (D) N-butyl-N-methyl-2-hydroxybenzylamine,

(E) N-pentyl-N-methyl-Z-hydroxybenzylamine,

(F) N-hexyl-N-methyl-2-'hydroxybenzylamine,

(G') N-isohexyl-N-methyl-2-hydroxybenzylamine, and (H') N-octyl-N-methyl-2-hyd-roxybenzylamine.

Example 5 By applying the process of Example SE to compounds of Example 1, there are obtained the following N,N-dimethyl 2 hydroxybenzylamines: 3 methoxy N,N- diimethyl 2 hydroxybenzylamine, 5 chloro N,N- dimethyl 2 -'hydr-oxybenzylamine, 5 bromo N,N dirnethyl 2 hydroxybenzylamine, N,N d'imethyl 2,5- dihydroxy benzylamine, 3,5 dichloro N,N dimethyl- 6 2-hydroxybenzylamine, and 5,6- benzo-N,N-d imcthy1-2- hydroxybenzylamine.

Example 6.3,4-dihydro-4-hydroxy-3 phenyl-2H- 1,3 -benzoxazin-2-one By substituting the methyl isocyanate of Example 1A by phenyl isocyanate and keeping the temperature at between 0 and 10 C., 3,4-dihydro-4-hydroxy-3-phenyl- 2H-l,3-benzoxazin-2-one was obtained, which after recrystallization from benzene had a melting point of 113- 114 C. (dec.) and the following elemental analysis:

Calcd. for C H NO C, 69.7; H, 4.59; N, 5.8. Found: C, 69.26; H, 4.68; N, 5.69.

Example 7.-3,4-dihydro-4-phenylcarbamyloxy-3- phenyl-2H- l ,3 benzoxazin-2-one To a solution of o-hydroxybenzaldehyde (12.2 g.; 0.10 mole), phenyl isocyanate (25.0 g.; 0.21 mole) and anhydrous diethyl ether ml.) was added triethylamine (1.0 ml.). A vigorous reaction took place and a White precipitate was formed. The mixture was heated under reflux for 2 hrs. After cooling to room temperature, the solid was filtered off, washed with diethyl ether, and dried. The yield was quantitative, M.P. 143-l45 (dec.). Recrystallization from benzene gave 3,4 dihydr-o- 4- phenylcarbamyloxy 3 phenyl 2H 1,3 benzoxazin- 2-one as a colorless product, M.P. 148-l49 C. (dec.).

Analysis.-Calcd. for C H N O C, 69.98; H, 4.48; N, 7.78. Found: C, 70.3; H, 4.8; N, 7.7.

By applying the process of Example 3B to 3,4-dihydro- 4 phenylcarbamyloxy 3 phenyl 2H 1,3 benzoxazin-t2-one there is obtained N-methyl-N-phenyl-2-hydroxybenzylamine.

I claim:

1. The process which comprises reacting, in the pres ence of a basic catalyst and an inert reaction medium, a 2-hydroxybenzaldehyde of the formula:

wherein R is selected from the group consisting of benzo and from Zero to not more than 4 members selected from the group consisting of alkyl of not more than 3 carbon atoms, alkoxy of not more than 3 carbon atoms, 'hydroxy, halogen, and nitro with a compound selected from the group consisting of phenyl isocyanate and a loweralkyl isocyanate to produce a compound of the formula:

7 3. The process according to claim 2 wherein 2-hydroxybenzaldehyde is reacted with methyl isocyanate by heating in the presence of triethylamine to obtain 3,4- dihydro 4 hydroxy 3 methyl 2H 1,3 bcnzoxazin-2-one, and hydrogenolytically cleaving the 3,4-dihydro 4 hydroxy 3 methyl 2H 1,3 benzoxazin- 2-0ne with lithium aluminum hydride to obtain N,N-di- :methyLZ-hydroxybenzylamine.

8 References Cited UNITED STATES PATENTS 3,296,259 1/1967 Strube 260-244 JOHN D. RANDOLPH, Primary Examiner.

R, T. BOND, Assistant Examiner. 

1. THE PROCESS WHICH COMPRISES REACTING, IN THE PRESENCE OF A BASIC CATALYST AND AN INERT REACTION MEDIUM, A 2-HYDROXYBENZALDEHYDE OF THE FORMULA: 